Synthesis and evaluation of nucleoside radiotracers for imaging proliferation

Graham Smith, Roberta Sala, Laurence Carroll, Kevin Behan, Matthias Glaser, Edward Robins, Quang Dé Nguyen, Eric O. Aboagye

Research output: Contribution to journalArticle

Abstract

Introduction: Uncontrolled proliferation is a fundamental characteristic of cancer, and consequently, imaging of tumor proliferative status finds interest clinically both as a diagnostic tool and for evaluation of response to treatment. Positron emission tomography (PET) radiotracers based on a nucleoside core, such as 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), have been extensively studied for this purpose. However, [18F]FLT suffers from poor DNA incorporation leading to occasional poor correlation of [18F]FLT tumor uptake with other proliferation indicators such as Ki-67 immunostaining. Methods: N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)thymidine ([18F]2) and N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-4'-thio-β-thymidine ([18F]3) were synthesized by click chemistry from [18F]fluoroethyl azide and by direct nucleophilic substitution of a tosylate precursor. Metabolic stability and phosphorylation potential of the radiotracers were evaluated in vitro and compared to [18F]FLT. Further, metabolic stability and biodistribution analysis of [18F]2 and [18F]3 were evaluated in vivo. Results: Stable isotope standards and radiochemistry precursors were synthesized by modification of existing literature procedures. [18F]2 and [18F]3 were synthesized in a radiochemical yield of 8%-12% (end of synthesis, non-decay corrected). Both nucleosides were stable to metabolic degradation by thymidine phosphorylase, and in vivo stability analysis showed only one metabolite for [18F]3. No phosphorylation of [18F]2 could be detected in HCT116 cell homogenates, and in the same assay, only minor (~8%) phosphorylation of [18F]3 was observed. Biodistribution in Balb/c mice indicated rapid clearance for [18F]2 and [18F]3 to a lesser extent. Conclusions: The favorable biodistribution and metabolic profile of [18F]3 warrant further investigation as a next-generation PET proliferation marker.

Original languageEnglish (US)
Pages (from-to)652-665
Number of pages14
JournalNuclear Medicine and Biology
Volume39
Issue number5
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

Fingerprint

Nucleosides
Phosphorylation
Positron-Emission Tomography
Thymidine
Radiochemistry
Click Chemistry
Thymidine Phosphorylase
HCT116 Cells
Neoplasms
Metabolome
Azides
Isotopes
alovudine
DNA

Keywords

  • [F]FLT
  • Click chemistry
  • Fluorine-18
  • Nucleosides
  • Proliferation

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Synthesis and evaluation of nucleoside radiotracers for imaging proliferation. / Smith, Graham; Sala, Roberta; Carroll, Laurence; Behan, Kevin; Glaser, Matthias; Robins, Edward; Nguyen, Quang Dé; Aboagye, Eric O.

In: Nuclear Medicine and Biology, Vol. 39, No. 5, 01.07.2012, p. 652-665.

Research output: Contribution to journalArticle

Smith, G, Sala, R, Carroll, L, Behan, K, Glaser, M, Robins, E, Nguyen, QD & Aboagye, EO 2012, 'Synthesis and evaluation of nucleoside radiotracers for imaging proliferation', Nuclear Medicine and Biology, vol. 39, no. 5, pp. 652-665. https://doi.org/10.1016/j.nucmedbio.2011.12.002
Smith, Graham ; Sala, Roberta ; Carroll, Laurence ; Behan, Kevin ; Glaser, Matthias ; Robins, Edward ; Nguyen, Quang Dé ; Aboagye, Eric O. / Synthesis and evaluation of nucleoside radiotracers for imaging proliferation. In: Nuclear Medicine and Biology. 2012 ; Vol. 39, No. 5. pp. 652-665.
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abstract = "Introduction: Uncontrolled proliferation is a fundamental characteristic of cancer, and consequently, imaging of tumor proliferative status finds interest clinically both as a diagnostic tool and for evaluation of response to treatment. Positron emission tomography (PET) radiotracers based on a nucleoside core, such as 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), have been extensively studied for this purpose. However, [18F]FLT suffers from poor DNA incorporation leading to occasional poor correlation of [18F]FLT tumor uptake with other proliferation indicators such as Ki-67 immunostaining. Methods: N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)thymidine ([18F]2) and N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-4'-thio-β-thymidine ([18F]3) were synthesized by click chemistry from [18F]fluoroethyl azide and by direct nucleophilic substitution of a tosylate precursor. Metabolic stability and phosphorylation potential of the radiotracers were evaluated in vitro and compared to [18F]FLT. Further, metabolic stability and biodistribution analysis of [18F]2 and [18F]3 were evaluated in vivo. Results: Stable isotope standards and radiochemistry precursors were synthesized by modification of existing literature procedures. [18F]2 and [18F]3 were synthesized in a radiochemical yield of 8{\%}-12{\%} (end of synthesis, non-decay corrected). Both nucleosides were stable to metabolic degradation by thymidine phosphorylase, and in vivo stability analysis showed only one metabolite for [18F]3. No phosphorylation of [18F]2 could be detected in HCT116 cell homogenates, and in the same assay, only minor (~8{\%}) phosphorylation of [18F]3 was observed. Biodistribution in Balb/c mice indicated rapid clearance for [18F]2 and [18F]3 to a lesser extent. Conclusions: The favorable biodistribution and metabolic profile of [18F]3 warrant further investigation as a next-generation PET proliferation marker.",
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T1 - Synthesis and evaluation of nucleoside radiotracers for imaging proliferation

AU - Smith, Graham

AU - Sala, Roberta

AU - Carroll, Laurence

AU - Behan, Kevin

AU - Glaser, Matthias

AU - Robins, Edward

AU - Nguyen, Quang Dé

AU - Aboagye, Eric O.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - Introduction: Uncontrolled proliferation is a fundamental characteristic of cancer, and consequently, imaging of tumor proliferative status finds interest clinically both as a diagnostic tool and for evaluation of response to treatment. Positron emission tomography (PET) radiotracers based on a nucleoside core, such as 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), have been extensively studied for this purpose. However, [18F]FLT suffers from poor DNA incorporation leading to occasional poor correlation of [18F]FLT tumor uptake with other proliferation indicators such as Ki-67 immunostaining. Methods: N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)thymidine ([18F]2) and N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-4'-thio-β-thymidine ([18F]3) were synthesized by click chemistry from [18F]fluoroethyl azide and by direct nucleophilic substitution of a tosylate precursor. Metabolic stability and phosphorylation potential of the radiotracers were evaluated in vitro and compared to [18F]FLT. Further, metabolic stability and biodistribution analysis of [18F]2 and [18F]3 were evaluated in vivo. Results: Stable isotope standards and radiochemistry precursors were synthesized by modification of existing literature procedures. [18F]2 and [18F]3 were synthesized in a radiochemical yield of 8%-12% (end of synthesis, non-decay corrected). Both nucleosides were stable to metabolic degradation by thymidine phosphorylase, and in vivo stability analysis showed only one metabolite for [18F]3. No phosphorylation of [18F]2 could be detected in HCT116 cell homogenates, and in the same assay, only minor (~8%) phosphorylation of [18F]3 was observed. Biodistribution in Balb/c mice indicated rapid clearance for [18F]2 and [18F]3 to a lesser extent. Conclusions: The favorable biodistribution and metabolic profile of [18F]3 warrant further investigation as a next-generation PET proliferation marker.

AB - Introduction: Uncontrolled proliferation is a fundamental characteristic of cancer, and consequently, imaging of tumor proliferative status finds interest clinically both as a diagnostic tool and for evaluation of response to treatment. Positron emission tomography (PET) radiotracers based on a nucleoside core, such as 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), have been extensively studied for this purpose. However, [18F]FLT suffers from poor DNA incorporation leading to occasional poor correlation of [18F]FLT tumor uptake with other proliferation indicators such as Ki-67 immunostaining. Methods: N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)thymidine ([18F]2) and N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-4'-thio-β-thymidine ([18F]3) were synthesized by click chemistry from [18F]fluoroethyl azide and by direct nucleophilic substitution of a tosylate precursor. Metabolic stability and phosphorylation potential of the radiotracers were evaluated in vitro and compared to [18F]FLT. Further, metabolic stability and biodistribution analysis of [18F]2 and [18F]3 were evaluated in vivo. Results: Stable isotope standards and radiochemistry precursors were synthesized by modification of existing literature procedures. [18F]2 and [18F]3 were synthesized in a radiochemical yield of 8%-12% (end of synthesis, non-decay corrected). Both nucleosides were stable to metabolic degradation by thymidine phosphorylase, and in vivo stability analysis showed only one metabolite for [18F]3. No phosphorylation of [18F]2 could be detected in HCT116 cell homogenates, and in the same assay, only minor (~8%) phosphorylation of [18F]3 was observed. Biodistribution in Balb/c mice indicated rapid clearance for [18F]2 and [18F]3 to a lesser extent. Conclusions: The favorable biodistribution and metabolic profile of [18F]3 warrant further investigation as a next-generation PET proliferation marker.

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KW - Nucleosides

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